Discussion
This series of patients illustrates both the promise and limitation of MEK inhibition with trametinib monotherapy for LCH. Specifically, patient 3 with MAP2K1 deletion and systemic LCH in the newborn period showed a complete and durable response to trametinib and is thriving with no active disease. On the other hand, patient 2 withBRAF deletion has had only a partial response to full dose trametinib.
As suggested by Allen et al., there is a significant difference between infants with isolated cutaneous LCH and infants who develop progressive, life-threatening disease as patient 3. 1 The misguided myeloid differentiation model proposed by Allen et al. would suggest that patient 3 developed MAP2K1 deletion early in fetal life, possibly in the yolk-sac progenitors or fetal liver monocytes.1
The misguided myeloid differentiation model also suggests that the origin of neurodegenerative LCH disease is from a hematopoietic cell clone. 1 Whether this is true only for BRAFp.V600E mutation or other MAPK pathway variants remains to be seen.7,8 So far none of our patients have shown neurodegenerative changes. McClain et al demonstrated BRAFp.V600E in peripheral mononuclear cells in patients with neurodegenerative LCH. 8 We did not have the capacity to evaluate the presence of the variants reported here in the peripheral blood of our patients.
Though most patients with pulmonary LCH are adults with a smoking history, our patients are younger (2 months – 18 years) with no smoking history. 4 Jouenne et al., in a large adult LCH group, noted the BRAF N486_P490del as the second most common variant after BRAF V600E mutation. This was especially seen in association with lung disease. 2
The dose and length of therapy of trametinib needed to inhibit the MAPK pathway in LCH is not established. A retrospective study of 21 pediatric LCH patients with MAPK pathway somatic mutation (BRAF p.V600E, n = 20; MAP2K1c .293_310del, n = 1) who received MAPK pathway inhibitors after failure of at least 1 prior therapy was recently reported by the NACHO-LIBRE Study Group. 9 They reported 86% response rate to therapy, and 6 patients in that group received trametinib either in combination with BRAF inhibitors or alone. The dose of trametinib in that report ranges from 0.0125-0.018 mg/kg or reported as 1 mg or 2 mg daily. Patient 21 in that report had an identical MAP2K1 deletion to our patient number 3. That patient had brief response to trametinib for 2 months before suffering progressive disease. 9 In contrast, our patient 3 had remarkable response to trametinib daily lasting almost 2 years. Lee et al. described a 36 year old female with similar BRAF p.N486_P490 deletion to our patients 1 and 2 who had a remarkable response to trametinib within 5 days including PET/CT negativity after 4 months and elimination of seizures within weeks. 5 The dose of trametinib was not reported. Notably, our patient 2 had partial response of lung disease on monotherapy with trametinib 2 mg daily.
Diamond et al. report that the MEK1/2 inhibitor cobimetinib (60 mg daily for 21 days of a 28-day cycle) resulted in remarkable response rate (89%) among adults with histiocytic disorders. 10 In that report a patient with LCH and BRAF N486_P490del did seem to have a complete response lasting 2 years, as did some of the patients with MAP2K1 mutations. It is certainly possible that cobimetinib is a better MEK inhibitor for LCH
In summary, 3 LCH patients are currently receiving monotherapy with trametinib for systemic LCH. Two have BRAF p.N486_P490del and one has MAP2K1 p.K57_G61del. These patients are tolerating therapy with low grade skin toxicity and tolerable elevations in CPK levels. Two (patients 1 & 3) are maintaining non-active disease (follow-up 18-22 months) and one (patient 2) who had partial response is stable with active disease (follow-up 12 months).